There is growing agreement that many complex cognitive functions (especially learning, memory, and emotional expression) are best understood as requiring an interaction among semi-independent neural circuits focused around a variety of limbic system structures, including the hippocampus, amygdala and limbic-associated regions of cortex. However, the functional development of these systems is only beginning to be understood. Depending on the specific neural substrates involved, even very similar learning, memory and emotional processing tasks appear to have different ontogenetic profiles. For example, it has been well established that the ability to form aversive associations with discrete cues, as demonstrated by auditory or visual classical fear conditioning, emerges prior to the ability to form emotional associations with physical environments, as demonstrated by contextual fear conditioning. Since aversive memories all depend upon the amygdala, but spatial and contextual memories uniquely depend on the hippocampus, such findings had been interpreted as suggesting that the hippocampus was relatively slow to develop. However, recent data from our lab presents two challenges to this idea. First, the ability to form a representation of the environment (dependent upon the hippocampus) is present early than previously believed. Further development is required prior to the ability to integrate these types of experiences with emotional events and to express fear to a particular environment. Moreover, the ability to express fear to an explicit cue (dependent on the amygdala) continues to increase for some time after its initial emergence, longer than previously believed. Thus, the data show that contrary to previous understanding, the hippocampus-dependent memory system is functional as early as day 17 in rats, and the amygdala-dependent system continues to mature. Using contextual and cued fear conditioning protocols, the current project examines the emergence of amygdala and hippocampus functionality and interactions by testing the novel hypothesis that it is slow-developing amygdala- hippocampus interactions that are responsible for the developmental delay. To test this hypothesis, the effects of behavioral manipulations, immediate-early gene expression, and temporary pharmacological inactivation will be examined on various aspects fear conditioning. Overall this project will elucidate the neural structures governing the use of physical environments to regulate aversive emotional expression in developing rats. PUBLIC HEALTH RELEVANCE: This project investigates the development of limbic system function. The focus is to create and examine a paradigm that can be used to assess the connectivity between major limbic system structures including the hippocampus and amygdala. Although relatively little is known about how they functionally interact in intact developing organisms, the connectivity between these structures appears to be altered in several developmental disorders including major psychoses, autism and anxiety disorders. Thus, in addition to advancing our understanding of typical development, these experiments will open the door for future studies that further elucidate the mechanisms underlying these disorders. Therefore, this project will provide data leading to a better understanding of limbic system development and the creation of better animal models of developmental disorders.